Inhibitors of secretion of hepatitis B virus antigens

Abstract

Pharmaceutical compositions of the invention comprise triazolopyrimidines useful for the treatment of hepatitis virus in a patient.

What is claimed is: 
     
       1. A pharmaceutical composition comprising:
 (a) an effective amount of one or more compounds of Formulas I or II, or an enantiomer, N-oxide, prodrug, protected derivative, stereoisomer or mixture of stereoisomers, or pharmaceutically acceptable salt or solvate thereof: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1 -R 4  are independently phenyl or Het, wherein each phenyl or Het is optionally substituted with at least one substituent independently selected from the group consisting of (C 1-7 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 2-7 )alkanoyl, (C 2-7 )atkanoyloxy, (C 3-12 )cycloalkyl, (C 1-7 )acyl, aryl, halo, OR a , trifluoromethoxy, trifluoromethyl, NO 2 , NR a R b , cyano, CONR a R b , SO m R a , S(O) m NR a R b , P(═O)(OR a )(R a ), and Het, wherein (C 1-7 )alkyl or (C 3-12 )cycloalkyl are each independently optionally substituted with from 1 to 5 aryl, Het, OR a , halo, NO 2 , NR a R b , cyano, CONR a R b , CO 2 R, SO m R a , S(O) m NR a R b , or P(═O)(OR a )(R a ); 
         X 1 -X 12  are independently a bond or a saturated or unsaturated alkylene group; 
         R a  and R b  are each independently H, (C 1-7 )alkyl, (C 3-12 )cycloalkyl, (C 2-7 )alkanoyl, (C 2-7 )alkanoyloxy, or aryl, or R a  and R b  together with a nitrogen to which they are attached form a Het; 
         m is 0, 1, or 2; 
         n is 0, 1, 2, 3, or 4; 
       
       
         
           
           
               
               
           
         
         and 
         (b) a pharmaceutically acceptable carrier. 
       
     
     
       2. A pharmaceutical composition according to  claim 1  wherein at least one of the compounds is:
 7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chlorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-(4-Chlorophenyl)-7-(4-isopropylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-(4-Chlorophenyl)-7-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(pyridin-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 cis-7-(2-Chloro-6-fluorophenyl)-5-(6-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 (R,S)-7-(2-Chloro-6-fluoro-phenyl)-5-(4-chloro-phenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 (S,R)-7-(2-Chloro-6-fluoro-phenyl)-5-(4-chloro-phenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine; 
 or a specific enantiomer or a pharmaceutically acceptable form thereof. 
 
     
     
       3. The composition of  claim 1  further comprising an antiviral compound. 
     
     
       4. The composition of  claim 2  further comprising an antiviral compound. 
     
     
       5. The composition of  claim 3 , wherein said antiviral compound is selected from the group consisting of nucleoside antiviral compounds, nucleotide antiviral compounds, and mixtures thereof. 
     
     
       6. The composition of  claim 4 , wherein said antiviral compound is selected from the group consisting of nucleoside antiviral compounds, nucleotide antiviral compounds, and mixtures thereof. 
     
     
       7. A method for treating a hepatitis virus in a patient comprising administering an effective amount of the composition of  claim 1  to a patient in need thereof. 
     
     
       8. The method of  claim 7 , wherein said hepatitis virus is selected from the group consisting of viruses of the hepadnaviridae family and hepatitis delta virus. 
     
     
       9. The method of  claim 8 , wherein said hepatitis virus is hepatitis B virus. 
     
     
       10. A method for treating a hepatitis virus in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 1 , such that administering said composition reduces the serum level of hepatitis B surface antigen (HBsAg) in said patient.